We propose to study the efficacy of Ecosystem Focused Therapy (EFT) in post-stroke depression (PSD), a disorder that afflicts a large number of stroke victims and increases mortality, cognitive impairment, and disability for years after stroke. EFT is a new, home-delivered intervention based on our integrative model of PSD, which originated from our clinical biology and treatment studies in late-life depression. It postulates two main paths to PSD. First, stroke and stroke-repair mechanisms contribute to metabolic changes mediating PSD. Second, a psychosocial storm stemming both from the patient's sudden disability and the change in the patient's needs and family life add a biological burden to this cascade of depressogenic events. EFT targets the psychosocial storm of PSD and focuses on the reciprocal interaction between the patient's abilities and the challenges of his/her ecosystem (family, specialized therapists). EFT follows a structured personalization approach based on the model of adaptive functioning, in which behavior is a function of the person's competence and the demands of the environment. Thus, EFT continuously calibrates the environment to the PSD patient's competence level and targets the PSD psychosocial storm through five integrated components: 1) It offers an action-oriented, new perspective about the patient's recovery. 2) It provides an adherence enhancement structure. 3) It offers a problem solving structure to the patient focusing on problems, valued by the patient, and pertinent to daily function. 4) It helps the family reengineer its goals, involvement, and plans o accommodate the patient's disability. 5) It coordinates care with specialized therapists with the goal to increase patient participation in rehabilitation and social activities. We will recruit 160 PSD patients within 3 months after stroke and randomly assign them to 10 weekly sessions and 4 booster sessions (over 1 year) of EFT or a comparison condition (Education on Stroke and Depression; ESD) both administered by trained social workers (MSW). Our Primary Hypotheses state that: Over a period of 12 weeks, EFT will lead to greater reduction than ESD in: H1) severity of depression; and H2) disability. Our Secondary Hypotheses postulate that: SH1) EFT will lead to higher remission (HAM-Dd10) rates than ESD by 12 weeks; and SH2) EFT participants will have lower scores of depression and disability and higher scores in quality of life than ESD at 26 and 52 weeks. Exploratory Analyses will examine whether disability and depression mediate the effect of each other and whether self-efficacy, behavioral activation, and adherence to rehabilitation recommendations and/or antidepressants mediate change in depression and disability. We will also explore whether clinical features of PSD and serotonin transporter genotypes moderate the efficacy of ESD.